The present invention relates to 5-aryl-1H-1,2,4-triazole compounds, to a process for their preparation and to pharmaceutical compositions containing them.
Non-steroidal antiinflammatory drugs (NSAIDs) exert most of their effects through inhibition of prostaglandin H synthase (PGHS), which mediates the conversion of arachidonic acid to prostaglandins. The first committed step in this process is the oxidative cyclisation of arachidonic acid to PGE2, which is followed by peroxide reduction to PGH2 at a second distinct binding site. PGHS, commonly known as cyclooxygenase or COX, exist as two isoforms, each with a distinct physiological role (Hla, T et al, Proc. Natl. Acad. Sci. USA. 1992, 89, 7384, Holtzman, H. J. et al, J. Biol. Chem 1992, 267, 21438; Herschman, H. R., Cancer Metastasis Rev. 1994, 13, 241). One isoform, COX-1, is constitutively produced in a variety of tissues and appears to be important in the maintenance of normal physiological functions including renal blood flow and gastric cytoprotection. The second isoform, COX-2, is induced by a variety of inflammatory stimuli and appears to be largely responsible for the high-level production of prostaglandins that results in inflammation (Masferrer, J. L. et al., Proc. Natl. Acad. Sci. USA 1994, 91, 3228; Vane, J. et al. Proc. Natl. Acad. Sci. USA. 1994, 91, 2046).
WO95/15318, WO95/15316, U.S. Pat. Nos. 5,434,178, 5,466,823, 5,504,215, 5,508,426 and 5,510,496 describe 1,5-diaryl-pyrazoles with in vitro and in vivo activities.
Some 1,5-diphenyl-1H-1,2,4-triazoles such as compound (a), having a moderate Cox-2 inhibitory activity and anti-inflammatory potency, which are not superior to that of known anti-inflammatory agents, have been described in Monatshefte fur Chemie 119, 349-353 (1998). 
3-cyano-1,5-diphenyl-1H-1,2,4-triazoles such as compound (b) reported in Chem. Pharm. Bull. 45(6), 987-995 (1997) are weak and non selective inhibitors of cyclooxygenase-1 and cyclooxygenase-2. 
It has now been found that some 5-aryl-1H-1,2,4-triazole compounds are surprisingly particularly selective and strong inhibitors of cyclooxygenase-2.
Accordingly one object of this invention is to provide 5-aryl-1H-1,2,4-triazole compounds, which have a potent and selective COX-2 inhibiting activity.
The 5-phenyl-1H-1,2,4-triazole compounds of this invention are represented by the following general formula (I): 
in which:
R1 is hydrogen; a (C1-C6)alkyl; a halo(C1-C6)alkyl; or a phenyl optionally substituted by one or several subsdtients selected from the group consisting of a (C1-C4)alkyl, a halogen, a halo(C1-C4)alkyl, a hydroxy, a (C1-C4)alkoxy, an amino, a mono- or di-(C1-C4)alkylamino, a (C1-C4)alkylcarbonylamino, a (C1-C4)alkylthiocarbonylamino, a (C1-C4)alkoxycarbonylamino, a (C1-C4)akoxythiocarbonylamino, a (C1-C4)alkylsulfonyl, a (C1-C4)alkylsulfonylamino, a methylenedioxy, a nitro and a cyano;
R2 is a (C1-C6)alkyl; a (C3-C8)cycloalkyl; a phenyl or a phenyl(C1-C4)alkyl in which the phenyl is optionally substituted by one or several substituents selected from the group consisting of a (C1-C6)alkyl, a halogen, a halo(C1-C4)alkyl, a hydroxy, a (C1-C4)alkoxy, an amino, a mono- or di-(C1-C4)alkylamino, a (C1-C4)alkylcarbonylamino, a (C1-C4)alkylthiocarbonylamino, a (C1-C4)alkoxycarbonylamino, a (C1-C4)alkoxythiocarbonylamino, a (C1-C4)alkylsulfonyl, a (C1-C4)alkylsulfonylamino, a methylenedioxy, a nitro and a cyano; or a heretoaromatic radical;
R3 is hydrogen; a halogen; a hydroxy; a (C1-C6)alkoxy; an amino; a mono- or di-(C1-C6)alkylamino; a (C1-C6)alkylcarbonylamino; a (C1-C6)alkylthiocarbonylamino; a (C1-C6)alkoxycarbonylamino; a (C1-C6)alkoxythiocarbonylamino; a nitro; or a cyano;
R4 is a (C1-C6)alkyl; an amino; a mono- or di-(C1-C6)alkylamino; a (C1-C6)alkylcarbonylamino; a (C1-C6)alkylthiocarbonylamino; a (C1-C6)alkoxycarbonylamino; or a (C1-C6)alkoxythiocarbonylamino; and its pharmaceutical acceptable salts.
The term xe2x80x9c(C1-C4)alkylxe2x80x9d or xe2x80x9c(C1-C6)alkylxe2x80x9d is understood as meaning a linear or branched hydrocarbon chain having 1 to 4 (respectively 6) carbon atoms such as for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or hexyl radical.
The term xe2x80x9chalo(C1-C4)- or (C1-C6)alkylxe2x80x9d is understood as meaning a (C1-C4) or (C1-C6)alkyl radical in which 1 to 7 hydrogen atoms have been substituted with 1 to 7 halogen atoms such as for example a trifluoromethyl, a 2,2,2-trifluoroethyl, a pentafluoroethyl, a chloromethyl or a bromomethyl radical.
The term xe2x80x9chalogenxe2x80x9d is understood as meaning a chlorine, bromine, iodine or fluorine atom.
The term xe2x80x9c(C3-C8)cycloalkylxe2x80x9d is understood as meaning a saturated monocyclic hydrocarbon having 3 to 8 carbon atoms such as for example a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl radical.
The term xe2x80x9cheteroaromatic radicalxe2x80x9d is understood as meaning a 5 or 6-membered monocyclic or 9 or 10-membered bicyclic aromatic heterocycles containing one or two heteroatoms chosen from N, S and O, such as for example a pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl or indazolyl radical.
Preferred compounds of formula (I) are those in which
R1 is hydrogen, a (C1-C6)alkyl, a halo(C1-C6)alkyl or a phenyl;
R2 is a (C3-C8)cycloalkyl; a phenyl optionally substituted by one or several substituents selected from the group consisting of a halogen, a (C1-C4)alkyl, a (C1-C4)alkoxy, a hydroxy, a nitro, a di(C1-C4)alkylamino, a (C1-C4)alkylsulfonylamino, a (C1-C4)alkylsulfonyl and a methylenedioxy; a phenyl(C1-C4)alkyl in which the phenyl is substituted by one or several substituents selected from the group consisting of a hydroxy, a (C1-C4)alkyl and a (C1-C4)alkoxy; or a 5- or 6-membered monocyclic aromatic heterocycle containing one or two nitrogen, sulfur and/or oxygen atoms;
R3 is hydrogen or a halogen;
R4 is a (C1-C6)alkyl, a (C1-C4)alkylcarbonylamino or an amino.
Especially preferred are the compounds of formula (I) in which R1 is a (C1-C4)alkyl or a halo(C1-C4)alkyl such as trifluoromethyl.
Also especially preferred are the compounds of formula (I) in which R2 is a phenyl optionally substituted by one or several substituents selected from the group consisting of a halogen, a (C1-C4)alkyl, a (C1-C4)alkoxy, a hydroxy, a nitro, a di(C1-C4)alkylamino, a (C1-C4)alkylsulfonylamino, a (C1-C4)alkylsulfonyl and a methylenedioxy.
Further especially preferred compounds of formula (I) are those in which R3 is hydrogen and those in which R4 is a (C1-C6)alkyl or an amino.
The following compounds are especially valuable:
1-(4-methoxy-phenyl)-3-methyl-5-(4-methylsulfonyl-phenyl)-1H-1,2,4-triazole
1-(4-methoxy-phenyl)-5-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole
1-(4-bromo-phenyl)-5-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole
1-(4-methylsulfonylamino-phenyl)-5-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole
1-(4-methoxy-phenyl)-5-(4-aminosulfonyl-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole.
The pharmaceutically acceptable salts of the compounds of formula (I) are non-toxic salts including (i) salts of compounds of formula (I) containing acidic groups, for example alkali metal salts or alkaline earth metal salts such as sodium salts, potassium salts, magnesium salts and calcium salts, and also salts with pharmaceutically acceptable quaternary ammonium ions or organic amines such as triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine and the like, and (ii). salts of compounds of the formula (I) which contain basic groups, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like or with organic carboxylic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid and the like.
The compounds of formula (I) are useful for the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, tendinitis, bursitis, burns, injuries, especially following surgical and dental procedure ID additi n, such compounds can inhibit cellular neoplastic transformations and metastasic tumor growth and hence can be used in the treatment of familial polyposis and cancer (colon, lung, oesophageal and gastric cancers). The compounds of formula (I) can also be useful for the treatment of dementia including pre-senile and senile dementia, and in particular, dementia associated with Alzheimer""s disease (i.e. Alzheimer""s dementia). The compounds of formula (I) also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labor and asthma.
By virtue of their high cyclooxygenase-2 (COX-2) inhibiting activity and/or their selectivity for inhibiting cyclooxygenase-2 over cyclooxygenase-1, the compounds of formula (I) prove useful as an alternative to conventional non-steroidal anti-inflammatory drugs (NSAIDs) particularly where such non-steroidal anti-inflammatory drugs may be contra-indicated such as in patients with peptic, ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; GI bleeding, coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding problems (including those relating to reduced or impaired platelet function); kidney disease (e.g. impaired renal function); those prior to surgery or taking anticoagulants; and those susceptible to NSAID-induced asthma.
Accordingly, another object of this invention relates to the use of the compounds of formula (I) or their pharmaceutically acceptable salts for the preparation of a medicament intended for the treatment of cyclooxygenase-mediated diseases, especially those diseases susceptible to treatment with NSAIDs, and those advantageously treated by an agent which selectively inhibits COX-2 in preference to COX-1.
The invention also relates to a method of treating the above-mentioned cyclooxygenase-mediated diseases comprising the administration to a subject in need thereof of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
For the treatment of any of these cydooxygenase mediated diseases, the compounds of formula (I) may be administered, for example, orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. These dosage forms are given as examples, but other dosage forms may be developped by those skilled in the art of formulation, for the administration of the compounds of formula (I). The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of humans, the compounds of formula (I) are useful in the treatment of warm-blooded animals such as mice, rats, horses, cattle sheep, dogs, cats, and the like.
A further object of this invention therefore relates to pharmaceutical compositions, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient
The pharmaceutical compositions comprising the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft gelatin capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may comprise one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets comprise the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in U.S. Pat. Nos. 4,256,108, 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions comprise the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitol monooleate. The aqueous suspensions may also comprise one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may comprise a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occuring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitol monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitol monooleate. The emulsions may also comprise sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise a demulcent, a preservative and flavoring and coloring agents.
The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents which may be employed water, Ringer""s solution and an isotonic sodium chloride solution can be mentioned. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the active ingredient. These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the active ingredient. Such materials are for example cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, and the like, comprising a compound of formula (I) are employed (for the purpose of this application, topical application shall include mouth washes and gargles).
Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration. For example, a formulation intended for the oral administration in humans may comprise from 0.5 mg to 5 g of active ingredient compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 weight percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 1000 mg of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The present invention further relates to processes for the preparation of the compounds of the formula (I). The compounds can be prepared by the sequences show below in reaction schemes I, II and III. 
According to scheme I the starting materials can be amide derivatives of the formula I. They can be prepared from the corresponding carboxylic acids by processes described in the literature (for example see Org. Synth. col I, 153). Their condensation with N,N-dimethyl-amides dimethyl acetal, as described in Synthesis, 119 (1980), leads to the N2-acyl-N1,N1-dimethylamidines 5. The condensation of the derivatives 5 with hydrazines in a polar solvent (e.g. methanol, ethanol or the like) yields the 1H-1,2,4-triazole compounds 9. One equivalent of an organic base is added if the hydrochloride salt of the hydrazine is used. The hydrazines are mainly commercially available or are prepared from the corresponding amines by methods known to those of ordinary skill in the art (Advanced organic chemistry, Jerry March, Wiley, 1985). Then oxidation with two equivalents of MCPBA in an inert solvent (e.g. chloroform) gives the 1H-1,2,4-triazole compounds Ia.
According to scheme II the starting materials can be alkylimidates 2 or their salts. The reaction of the alkylimidate with the benzoylchloride 4 in a presence of an organic base like triethylamine leads to the N-acylimidate 6. Such method is described in Synthesis, 483 (1983). The reaction is carried out at room temperature in a non polar solvent like methylene chloride, chloroform or toluene. The cyclisation of the N-acylimidate 6 with hydrazines to give the 1H-1,2,4-triazole compounds 9 takes place at room temperature without catalyst in a non polar solvent like methylene chloride. One equivalent of an organic base (like triethylamine) is added if the hydrochloride salt of the hydrazine is used. The oxidation step like in scheme I yields the 1H-1,2,4-triazole compounds Ia.
According to scheme III the starting materials can be amidine derivatives 3 or their salts. They are commercially available or can be prepared by processes described in the literature (G. V. BOYD, the chemistry of amidines and imidates, Wiley, vol 2, chapter 7, 339, 1991). The reaction of hydrazines with the amidine derivatives 3 is carried out at room temperature in a polar solvent (e.g. methanol or ethanol) yielding the amidrazones 7. The condensation of the amidrazones 7 with the benzoyl chloride 4 in the presence of an organic base like pyridine leads to 1H-1,2,4-triazole compounds 9. The reaction take place preferably at the reflux temperature of a non polar solvent like dioxane. The oxidation step like in scheme I yields the 1H-1,2,4-triazole compounds Ia.
The treatment of the arylmethylsulfones Ia with a base and triethylborane gives the corresponding rearranged sulfonic acids which are converted to the arylsulfonamides Ib during oxidative amination workup. Such method are described by H. Chuang, E. J. Reinhard and D. B. Reitz in Tetrahedron letters, 35 (39), 7201-7204, (1994). The arylmethylsulfones Ia are deprotonated with a small excess of a base like ethylmagnesium chloride at low temperature (e.g. 0xc2x0 C.) in an inert solvent like THF and then are treated by triethylborane at the reflux temperature for several hours. Treatment with hydroxyamine-O-sulfonic acid at room temperature yields the arylsulfonamides Ib.
The sulfonamides Ib are treated with the acetyl chloride in acetic acid to give the acylsulfonamides Ic.
The invention will now be illustrated by the following examples and tests.